After Merrifield published the first solid-phase reaction in his prominent paper (Merrifield, 1963), describing the synthesis of a peptide via attachment of amino acids to a polymer backbone, the concept became the basis for automated peptide synthesis (Cabilly, 1998). With the advent of combinatorial chemistry, there has been an explosion of attention to solid phase chemistry during the last decade, in which the scope of this technique was expanded to other fields including small molecules (Blaney et al., 2002; Jung, 1999; Dorwald, 2000; Dolle et al., 1999; Dolle, 2000; Dolle, 2001), carbohydrates (Plante et al., 2001; Kanemitsu et al., 2002), and catalysts (Copeland et al., 2001; Jarvo et al., 2001). In addition to the conventional solid phase chemistry, in which the growing compound is loaded and modified on the solid support, after which the final product is cleaved from the solid support, solid phase reagent approach is an attractive alternative method (Ley et al., 2000). In this case, the core structure of the library molecule resides in the solution, while solid phase reagents are added to cause the reaction to proceed, and are then removed from the reaction mixture by filtration.
In particular, polymeric active ester reagents are known useful tools for amide/sulfonamide library synthesis (Kim, 1999; Chang et al., 2002; Salvino et al., 2000; Hahn et al., 1998; Parlow et al., 1995;.Masala et al., 1999) and for labeling reagents (Adamczyk et al., 1999; Adamczyk et al., 1999; Katoh et al., 1999; Chang et al., 1999). Most of the reported functionalities, such as nitrophenol (Cohen, 1984), N-hydroxysuccinimide (NHS) (Adamczyk et al., 1999a; Adamczyk et al., 1999b; Katoh et al., 1999), HOBt (1-hydroxybenzotriazole) (Dendrinos. et al., 1998; Pop et al., 1997), tetrafluorophenol (TFP) (Salvino et al., 1000), and Kaiser oxime (Scialdone et al., 1998; Lumma et al., 1998), have been attached to a polystyrene resin solid support by a Feidel-Crafts reaction (Cohen et al., 1984; Scialdone et al., 1998) or to a thiol resin by a maleimide linker (Adamczyk et al., 1999a; Adamczyk et al., 1999b; Katoh et al., 1999), thus limiting the selection of resin compositions and also limiting the reaction conditions to hydrophobic organic solvents.
To overcome this limitation, the present inventors previously studied an amide bond formation of tetrafluorohydroxybenzoic acid (Salvino et al., 2000) to a variety of compositions of aminomethylresins, and successfully compared the relative kinetic behaviors (Walsh et al., 2002). A similar strategy was applied in preparing TantaGel based HOBt, NHS, and TFP, and an amide forming reaction in aqueous media was demonstrated (Corbett et al., 2002). In aqueous media, the rate of a side reaction, hydrolysis over the desired aminolysis, was dependent on the reactivity of the active ester functionality as well as other reaction conditions. While TFP was the most favorable for the aminolysis with a minimum of hydrolysis among the resins compared, it would be useful to have a variety of activated esters as a toolbox for individual applications.